We have developed a multidisciplinary program to investigate genetic events leading to childhood cancer using genetic epidemiologic, cellular, and molecular techniques. The hypotheses are based-on a multi-stage model for cancer, and are tested in two model childhood and adolescent cancers, sarcomas and Wilms' tumor of the kidney. For each tumor type, there are specific genes that have been identified that may be altered both as germline mutations and as tumor-specific mutations. There is also significant evidence for genetic heterogeneity in the etiology of each tumor. The underlying themes of the program include characterizing the tumor types with respect to a multi-stage model, determination of the heritable contribution to each tumor, analysis of germline and somatic mutations by type and mechanism, and determination of the implications of germline mutations for the patients and their families. The findings from this program should provide insights into the mechanisms of carcinogenesis as well as guidelines for clinical programs for patients at high risk of cancer.